Polymeric materials have been widely used for implants or other biomedical applications, since they bear close resemblance to natural tissue components such as collagen, which allows direct bonding with other substances. Decades of peptide research have created a wide variety of biomedically useful polypeptides. However, they still are the most underrated and underused polymers considering their impressive properties, which include infusibility, mechanical strength and adhesive capability due to a highly flexible backbone and many functional side chains.
In recent years collagen, laminin, fibrin and fibronectin have been extracted, purified and marketed as tissue and cellular adhesion promoters. Synthetic poly-D-lysine and poly-L-lysine have also been sold for such purposes. But, significant inadequacies exist which limit the usage of such polymers such as: (a) they function with only limited types of substrates or are effective only for specific cell types; and (b) potential health hazards exist in the case of fibrin and fibronectin from human blood.
More recently, Waite and Tanzer, Science, Vol. 212, pp. 1038-1040 (1981) identified some of nature's most powerful adhesives, bioadhesive polyphenolic proteins, secreted by marine mussels which live under water and routinely cope with the forces of surf and tides. The naturally-occurring bioadhesive polyphenolic protein is produced and stored in the exocrine phenol gland of the mussel and is deposited onto marine surfaces by the mussel's foot during the formation of new adhesive plaques. The natural bioadhesive polyphenolic protein can be extracted and purified according to the procedures set forth in the Journal of Biological Chemistry, Vol. 258, pp. 2911-2915 (1983) or U.S. Pat. No. 4,496,397.
The utility of the natural bioadhesive polyphenolic protein extracted from the mussel is limited by the quantities that can be obtained. Amounts sufficient for low volume research and certain medical applications are now available.
The consensus decapeptide, which forms the repeating unit of the bioadhesive polyphenolic protein, can be obtained and polymerized in accordance with the procedure set forth in U.S. Pat. No. 4,585,585 The synthetically derived bioadhesive polyphenolic proteins exhibit adhesive characteristics, but suffer from the limitation that the obtainable molecular weight is only about 10,000 to 20,000, thereby limiting the adhesive strength thereof. Additionally, the polymerization of the decapeptides can be complicated by uncontrolled side reactions and the difficulty of efficiently de-blocking the protected amino acids. Therefore, such synthetic materials cannot be employed in many applications where greater adhesive strength is required.
With the exception of poly D-lysine and poly-L-lysine, the polypeptide adhesives must be extracted from biological sources. Synthetic polymers would usually be preferred to avoid the possible introduction of biologically derived, trace, but hazardous, contaminants.
Poly-D-lysine and poly-L-lysine, which can be synthesized to provide high molecular weight substances at a reasonable cost, were not found to be very effective for tissue adhesion. Similarly, the decapeptide oligomer of the bioadhesive polyphenolic protein does not have satisfactory adhesive properties and several attempts to polymerize the decapeptide employing classic sequence polymerization could not produce a high enough degree of polymerization to provide a decapeptide polymer with adhesive properties comparable to the natural bioadhesive polyphenolic protein extracted from the mussel.
Surprisingly, it now has been found that the stereochemistry of the decapeptide oligomer is not essential to the adhesive behavior of the bioadhesive polyphenolic protein. It has also unexpectedly been found that a polymer need only contain a certain amount of 3,4-dihydroxyphenylalanine (Dopa) rather than the entire decapeptide sequence in order to exhibit excellent adhesivity. Still further, it has now been found that the molecular weight of the polymer is of critical importance as is the cationic character of the backbone polymer and the final graft copolymer.
Accordingly, it is the primary object of the present invention to provide amino acid and/or peptide-containing graft copolymers which exhibit strong adhesive activity.
A further object of the present invention is to provide a flexible approach to the synthesis of custom-designed amino acid and/or peptide-containing graft copolymers suitable for specific end use applications and/or surfaces.
A still further object of the present invention is to reproducibly synthesize a graft copolymer with a particular molecular weight, dihydroxyphenylalanine (Dopa) content and adhesivity.